Interleukin 10 (IL-10), a cytokine produced by T lymphocytes, was first identified by its ability to inhibit interferon gamma (IFN-.gamma.) and IL-2 synthesis by mouse and human T lymphocytes. Fiorentino et al., 1989, J. Exp. Med. 170:2081-2089; Moore et al., 1990, Science 248:1230-1252; Vieira et al., 1991, Proc. Natl. Acad. Sci. USA 88:1172-1177. IL-10 was subsequently shown to be produced by B cells (O'Garra et al., 1990, Internat. Immunol. 2:821-828) and macrophages (Fiorentino et al., 1991, J Immunol. 147:3815-3822).
IL-10 exerts a wide range of effects on a variety of cell types. IL-10 inhibits the synthesis of a wide spectrum of cytokines produced by T cells and monocytes. In addition to inhibiting the synthesis of IFN-.gamma. and IL-2, IL-10 has also been shown to inhibit production of the monokines IL-1.alpha., IL-1.beta., IL-6 and TNF.alpha. de Waal et al., 1991, J. Exp. Med. 174:1209-1217. IL-10 has growth promoting effects on murine thymocytes and T cells (MacNeil et al., 1990, Immunol. 145:4167) and mast cells (Thompson-Snipes et al., 1991, J Exp. Med. 173:507-512), and it stimulates cytotoxic T-cell development (Chen and Zlotnik, 1991, J. Immunol. 147:528-533).
Mouse and human IL-10 have high sequence similarity with a protein encoded by an open reading frame in the Epstein-Barr Virus. The expression product of this open reading frame, named viral IL-10, also has the capacity to inhibit cytokine synthesis. Moore et al., 1990, Science 248:1230-1252; Vieira et al., 1991, Proc. Natl. Acad. Sci. USA 88:1172-1177.
Several cytokines, including IL-2, IFN-.gamma. and TNF.alpha., have been shown to regulate the mixed lymphocyte reaction (MLR). Shevach, 1985, Annu. Rev. Immunol. 3:397; Fidelus et al., 1982, Transplantation 34:308; Tadmori et al., 1985, J. Immunol. 134:4542-4550; Tadmori et al., 1986, J. Immunol. 136:1155-1162; Novelli et al, 1991, 147:1445-1450; Landolfo et al., 1985, Science 229:176-2180; Shalaby et al., 1988, J. Immunol. 141:499-505. It has been reported that IFN-.gamma. may pay an important role in MLR graft rejection. Novelli et al., 1991, J. Immunol. 147:1445-1450; Landolfo et al., 1985, Science 229:176-180. Antibodies to IFN-.gamma. or to TNF (Shalaby et al., 1988, J. Immunol 141:499-505) have been shown to block MLR-induced proliferation. In these studies it was found that antibodies to IFN-.gamma. suppressed the MLR in human systems as well as allograft reactivity in vitro and in vivo in the mouse.
International Application Publication No. WO 93/17698 discloses the use of IL-10 to suppress tissue graft rejection. The use of both human IL-10 and viral IL-10 is described.
Cyclosporin (also known as cyclosporin A; CSA), a cyclic peptide produced by the fungus Tolypocladium inflatum Gams and other fungi imperfecti, has cytokine inhibition ability. It has been found that inhibition of IL-2 production by cyclosporin (Shevach, 1985, Annu. Rev. Immunol. 3:397; Fidelus et al., 1982, Transplantation 34:308), or an antibody of CD2 (Tadmori et al., 1985, J. Immunol. 134:4542-4550) depresses T-cell proliferation induced by a MLR (Tadmori et al., 1986, J. Immunol. 136:1155-1162). CSA suppresses in vivo and in vitro cell-mediated responses (Fidelus et al., 1982, Transplantation 34:308-311) and is currently being used in most organ transplantation immunosuppressive protocols. CSA prolongs survival of allogeneic transplants involving skin, heart, kidney, pancreas, bone marrow, small intestine and lung and is also known to suppress graft-versus-host disease (GVHD) and delayed-type hypersensitivity. A problem with CSA, however, is organ toxicity. High doses of CSA can cause profound and irreversible nephrotoxicity as well as hepatoxicity and cardiotoxicity. There thus exists a need for an immunosuppressant treatment method that will allow administration of lower levels of CSA, thereby reducing the toxic effects of this agent.